Memory CD8+ T cells provide essential specific immunity against previously encountered antigens, and formation of such cells is a fundamental goal of vaccination. Effective CD8+ T cell memory is thought to require cells that persist at elevated frequencies long after antigen clearance, engage in rapid and robust expansion after reencounter with antigen and quickly re-acquire effector functions after re-stimulation. The overall focus of this proposal is to extend preliminary studies that define a special population of memory CD8 T cells that carry out highly efficient protective immunity against various pathogens - to determine how they achieve this protective effect, how this population of cells is maintained, and how these cells relate to populations arising in mice that arise naturally (following exposure to natural mouse pathogens) in order to understand how these cells relate to natural immunity.